Carcinoma of the ampulla of Vater is a malignant tumor arising in the last centimeter of the common bile duct, where it passes through the wall of the duodenum and ampullary papilla. Treatment fails in nearly 70% of patients with poor prognostic features.
Signs and symptoms
The signs and symptoms of ampullary carcinoma include the following:
Courvoisier gallbladder (ie, a distended, palpable gallbladder in a patient with jaundice)
Fever, particularly when the biliary tract has been explored previously (eg, after common duct exploration for stones)
See Clinical Presentation for more detail.
Routine laboratory studies include the following:
Complete blood count
Liver function studies: Prothrombin time, bilirubin (direct and indirect), transaminases, and alkaline phosphatase
CA 19-9: Serum tumor marker that is often elevated in pancreatic malignancies and may have a role in assessing response to therapy and/or predicting tumor recurrence
Carcinoembryonic antigen (CEA): A nonspecific tumor marker that is sometimes elevated in pancreatic malignancies; it may have a role in assessing response to treatment or predicting tumor recurrence
Ultrasonography of the abdomen
Abdominal ultrasonography is the initial study to evaluate the common bile duct or pancreatic ducts
Dilatation of these ducts is essentially diagnostic for extrahepatic obstruction
Biliary or pancreatic ductal dilatation can explain abdominal pain, even in patients with localized and noninvasive disease
10-15% of patients with normal common bile duct findings on ultrasonography demonstrate extrahepatic biliary obstruction on a computed tomography (CT) scan
Ultrasonography and CT scanning can help reveal metastatic disease in the liver or regional lymph nodes
CT scanning of the abdomen and/or pelvis
Obtain a CT scan to evaluate the local region of interest and evaluate for possible metastases
CT scanning often demonstrates a mass but is not helpful in differentiating ampullary carcinoma from tumors of the head of the pancreas or periampullary region; if the lesion is smaller than 2 cm, pancreatic or bile duct dilation may be the only abnormalities noted on the CT scan
Such findings are highly suggestive of pancreatic malignancy and require further evaluation, usually with endoscopic retrograde cholangiopancreatography (ERCP)
Dynamic CT scanning (ie, high-speed scans obtained during rapid intravenous administration of iodinated contrast material) can reveal tumor involvement of the vasculature
Other imaging studies
ERCP: Obtain ERCP to evaluate the ductal architecture further
Chest radiography: Obtain a chest radiograph to complete the workup (ie, for staging purposes)
Positron emission tomography (PET) or PET-CT scanning: PET or PET-CT scans can detect metastases that are too small to be reliably detected on a CT scan
See Workup for more detail.
The standard surgical approach to the treatment of ampullary carcinoma is pancreaticoduodenal resection (Whipple procedure). The procedure involves en bloc resection of the gastric antrum and duodenum; a segment of the first portion of the jejunum, gallbladder, and distal common bile duct; the head and often the neck of the pancreas; and adjacent regional lymph nodes.
The operative mortality rate for pancreaticoduodenectomy was at one time reported to be approximately 20%, but several hospital centers have since reported large series with operative mortality rates in the range of 5%.
Carcinoma of the ampulla of Vater is a malignant tumor arising in the last centimeter of the common bile duct, where it passes through the wall of the duodenum and ampullary papilla. The pancreatic duct (of Wirsung) and common bile duct merge and exit by way of the ampulla into the duodenum. The ductal epithelium in these areas is columnar and resembles that of the lower common bile duct.
Adenocarcinoma of the ampulla of Vater is relatively uncommon, accounting for approximately 0.2% of gastrointestinal tract malignancies and approximately 7% of all periampullary carcinomas.
The periampullary region is anatomically complex, representing the junction of 3 different epithelia, pancreatic ducts, bile ducts, and duodenal mucosa. Grossly, carcinomas originating in the ampulla of Vater can arise from 1 of 4 epithelial types: (1) terminal common bile duct, (2) duodenal mucosa, (3) pancreatic duct, or (4) ampulla of Vater.
Distinguishing between true ampullary cancers and periampullary tumors is critical to understanding the biology of these lesions. Each type of mucosa produces a different pattern of mucus secretion. In a complete histochemical study, Dawson and Connolly divided acid mucins into sulphomucins and sialomucins; in general, ampullary cancers produce sialomucins, whereas periampullary tumors secrete sulfated mucins. These researchers demonstrated that ampullary tumors secreting sialomucins had a better prognosis (100% vs 27% 5-y survival rate). Other investigators have confirmed the prognostic power of the pattern of mucin secretion.
Carter et al suggest that, histologically, ampullary tumors can be classified as either pancreaticobiliary or intestinal, and that the clinical behavior of these tumors reflects this classification; the course of intestinal ampullary adenocarcinomas is similar to that of their duodenal counterparts, whereas pancreaticobiliary tumors follow a more aggressive course, similar to that of pancreatic adenocarcinomas.
Immunohistochemical stains for expressions of carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, Ki-67, and p53 have been studied for prognostic power. In a series of 45 patients, expression of CA 19-9 labeling intensity and apical localization both were statistically significant predictors of poor prognosis. The 5-year survival rates were markedly different between tumors that expressed CA 19-9 and those that did not (36% vs 100%). CEA expression also might be a marker for prognosis, but it is much weaker. Ki-67 and p53 were not demonstrated to have an effect on outcome. Research along these avenues ultimately might provide the rationale for discriminative administration of adjuvant therapy.
Adenocarcinoma of the ampulla of Vater is a relatively uncommon tumor that accounts for approximately 0.2% of gastrointestinal tract malignancies and approximately 7% of all periampullary carcinomas. A review of data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program found 5,625 cases of ampullary cancer between 1973 and 2005; the frequency of the disease has been increasing since 1973.
Pancreaticoduodenectomy is a formidable operation, and the morbidity and mortality rates associated with this procedure historically have been high.
Until recently, the operative mortality rate was reported to be approximately 20%. In the past few years, several centers have reported large series with an operative mortality rate in the range of 5%. A recent review of the last 130 pancreaticoduodenectomies performed at Stanford University Medical Center over the last 5 years revealed an operative mortality rate of 3%. This improvement can be attributed to increased surgical experience, improved patient selection, improved anesthesia, better preoperative imaging, and general improvement in the management of ill patients.
The morbidity rate associated with the surgery is approximately 65%. In some series, 13% of patients required a repeat laparotomy for complications. Patients may experience fistula formation, delayed intestinal function, pneumonitis, intra-abdominal infection, abscess, or thrombophlebitis. Marginal ulceration, diabetes, pancreatic dysfunction (steatorrhea), and gastrointestinal motility disorder all can manifest as late complications of the surgery.
Because carcinoma of the ampulla of Vater is relatively uncommon, studies of the patterns of occurrence among different ethnic groups have not been conducted.
Ampullary cancer is more common in men, according to the National Cancer Institute’s SEER Program.
Routine laboratory studies include a complete blood cell count, electrolyte panel, liver function studies (prothrombin time, bilirubin [direct and indirect], transaminases, alkaline phosphatase), CEA, and CA 19-9.
A rising bilirubin level due to obstructive jaundice often is the sole presenting sign.
CA 19-9 is a serum tumor marker that is often elevated in pancreatic malignancies and might have a role in assessing response to therapy, predicting tumor recurrence, or both.
CEA is another nonspecific tumor marker that sometimes is elevated in pancreatic malignancies. It might have a role in assessing response to treatment or predicting tumor recurrence. Because CEA also is elevated in patients with other gastrointestinal malignancies (eg, colon and rectal in particular), exclude the possibility of a second primary tumor in these patients.
Abdominal ultrasound is the initial study to evaluate the common bile duct or pancreatic ducts.
Dilatation of these ducts essentially is diagnostic for extrahepatic obstruction.
Biliary or pancreatic ductal dilatation can explain abdominal pain, even in patients with localized and noninvasive disease.
However, 10-15% of patients with normal common bile duct findings on ultrasonography demonstrate extrahepatic biliary obstruction on a computed tomography (CT) scan.
Both ultrasound and CT can help reveal metastatic disease in the liver or regional lymph nodes.
CT scan of the abdomen and/or pelvis
Obtain a CT scan image to evaluate the local region of interest and evaluate for possible metastases.
CT scan often demonstrates a mass but is not helpful in differentiating ampullary carcinoma from tumors of the head of the pancreas or periampullary region. If the lesion is smaller than 2 cm, pancreatic or bile duct dilation might be the only abnormalities noted on CT scan.
Such findings are highly suggestive of pancreatic malignancy and require further evaluation, usually with endoscopic retrograde cholangiopancreatography (ERCP).
Dynamic CT scanning (ie, high-speed scans obtained during rapid intravenous administration of iodinated contrast material) can reveal tumor involvement of the vasculature. Some centers still rely on angiography to help identify patients with potentially resectable disease.
Endoscopic retrograde cholangiopancreatography
Obtain ERCP to evaluate the ductal architecture further.
Findings on ERCP that suggest pancreatic cancer include irregular pancreatic duct narrowing, displacement of the main pancreatic duct, destruction or displacement of the side branches of the duct, and pooling of contrast material in necrotic areas of tumor.
Chest radiograph: Obtain a chest x-ray film to complete the workup (ie, for staging purposes).
Positron emission tomography (PET) or PET-CT scans: These scans have been widely adopted in the author's clinic as a means of imaging the metabolic activity of a particular tumor. PET or PET-CT scans can detect metastases that are too small to be reliably detected on a CT scan.
Over the years, multiple systems for staging this tumor have been proposed.
Martin proposed a 4-stage system, as follows:
Stage I - Vegetating tumor limited to the epithelium with no involvement of the sphincter of Oddi
Stage II - Tumor localized in the duodenal submucosa without involvement of the duodenal muscularis propria but possible involvement of the sphincter of Oddi
Stage III - Tumor of the duodenal muscularis propria
Stage IV - Tumor of the periduodenal area or pancreas, with proximal or distal lymph node involvement
The classification system of Yamaguchi and Enjoji is similar to the Martin classification.
Talbot et al devised a system that scored tumors according to the degree of infiltration (from 1-4 according to increasing infiltration) and according to tumor differentiation (from 1-3 for well, moderately, and poorly differentiated tumors), the sum of which separated the patients into 2 groups (scores 2-4 and scores 5-7).
The currently accepted American Joint Committee on Cancer staging system for ampullary carcinoma emphasizes the importance of pancreatic invasion and lymph node metastases (see below and see Table 1, below). Size has little impact on tumor stage. The definition of primary tumor (T), regional lymph node (N), and remote metastases (M) for classification and staging of thyroid node metastasis and staging for cancer of the ampulla of Vater is as follows:
TX – Primary tumor cannot be assessed
T0 – No evidence of primary tumor
Tis – Carcinoma in situ
T1 – Tumor limited to ampulla of Vater
T2 – Tumor invades duodenal wall
T3 – Tumor invades less than 2 cm into pancreas
T4 – Tumor invades more than 2 cm into pancreas or other organs
Regional lymph nodes
NX – Regional lymph nodes cannot be assessed
N0 – No regional lymph node metastases
N1 – Lymph node metastases
MX – Presence of distant metastases cannot be assessed
M0 – No distant metastases
M1 – Distant metastases
Table 1. Staging of Ampullary Cancers by the TNM System
The standard surgical approach is pancreaticoduodenal resection (Whipple procedure). The procedure involves en bloc resection of the gastric antrum and duodenum; a segment of the first portion of the jejunum, gallbladder, and distal common bile duct; the head and often the neck of the pancreas; and adjacent regional lymph nodes.
In a review of 450 cases of surgical resection of ampullary adenoma or adenocarcinoma at Johns Hopkins, Winter et al found that 96.7% of the patients had undergone pancreaticoduodenectomy rather than local excision. These researchers concluded that pancreaticoduodenectomy should be the preferred approach for most ampullary neoplasms that require surgical resection, given that nearly 30% of the Johns Hopkins patients with T1 disease had lymph node metastases. Factors associated with the presence of lymph node metastasis included tumor size ≥ 1 cm (odds ratio [OR] 2.1), poor histologic grade (OR 4.8), perineural invasion (OR 3.0), microscopic vessel invasion (OR 6.6), and depth of invasion > pT1 (OR 4.3; all P < 0.05). Specifically, risk of lymph node metastasis increased with T stage (T1, 28.0%; T2, 50.9%; T3, 71.7%; T4, 77.3%; P < 0.001).[7, 8]
Results after radical resection of ampullary of Vater carcinoma have been improving. During the past decade, 5-year survival rates have ranged from 20-61%, averaging higher than 35%. The reported mortality rates from this operation are decreasing. A summary follows in Table 2.
Table 2. Results of Pancreaticoduodenal Resection for Carcinoma of the Ampulla of Vater
In a review of more than 1100 patients published in a surgical series, Howe et al reported that the overall rate of resectability was 82%. This most likely overestimates the true resectability rate because patients in whom radiologic studies identify unresectable disease often are not included in retrospective surgical series.
A review of cases from Veterans Affairs hospitals across the United States by el-Ghazzawy et al revealed that only 63% of presenting patients undergo surgery for cure. At disease presentation, 30-50% have involved lymph nodes.
A few studies have been conducted on the pattern of lymphatic spread of ampullary cancer. These studies have been difficult to interpret because of the lack of standardized nomenclature for lymph node groups, variability in the degree of superior mesenteric lymph node dissection, and the small number of patients.
Shirai and colleagues meticulously reviewed 21 cases of ampullary cancer and documented the pattern of lymphatic spread. The site of greatest nodal involvement, the first echelon group, is the posterior pancreaticoduodenal nodal group. The nodal groups surrounding the inferior pancreaticoduodenal artery were the superior mesenteric lymph nodes involved most often. Finally, the para-aortic lymph node groups were involved in 3 patients with resectable disease.
Kayahara reported that the inferior pancreaticoduodenal nodes (13b) and the superior mesenteric nodes (14) were the groups most often involved with metastatic carcinoma.
Because of the mortality and morbidity associated with pancreaticoduodenectomy, physicians have been interested in performing local excisions of cancers of the ampulla of Vater to avoid a major resection.
Transduodenal excision of ampullary tumors has been proposed as an intermediate option between radical resection and palliative bypass for high-risk patients. Some have argued that this approach is simpler, is better tolerated, and might provide a comparable cure rate (mortality rate 8-13%, 5-y survival rate 0-43%). This approach generally has been reserved for poor operative candidates (eg, elderly patients, those with other comorbid conditions) with favorable tumors (generally < 2 cm, polypoid). Unfortunately, this approach compromises local control. The local failure rate for the 18 cases collected from the contemporary literature was 50%. One patient required 3 repeat excisions for local recurrence.
Recent reviews of single-institution surgical experiences of ampullary cancer have focused on the identification of histopathologic features associated with prognosis and survival. Retrospective review, small patient numbers, and long periods of enrollment limit what can be learned from these studies. However, common themes emerge from these published clinicopathologic analyses.
Survival after surgical resection is related to the extent of local invasion of the primary lesion, lymph node involvement, vascular invasion, perineural invasion, cellular differentiation, and uninvolved surgical margins. Even a single lymph node with evidence of metastatic carcinoma portends a poor outcome with surgery alone. Exactly which factors are truly independent remains controversial.
el-Ghazzawy et al reviewed experiences in the US Department of Veterans Affairs hospitals from 1987-1991, during which time 123 patients were diagnosed with ampullary cancer. In the group that underwent surgical resection, perineural invasion, microlymphatic invasion, vascular invasion, or tumor differentiation did not independently influence survival when the tumors were controlled for stage.
Yamaguchi et al compared 18 variables among 8 long-term survivors and 12 short-term survivors with ampullary cancer and found that only perineural invasion and histologic grade were significant.
In a retrospective review of 46 consecutive cases of ampullary carcinoma, multivariate analysis by Sudo et al showed perineural invasion to be a significant independent predictor of poor prognosis (P = 0.024). On univariate analysis, other significant predictors of poor prognosis were T3 and T4 tumors (ie, pancreatic parenchymal invasion) (P < 0.001) and lymph node metastasis (P = 0.01).
Multivariate analysis of 302 cases by Lowe et al also showed that perineural invasion is associated with lower survival (hazard ratio [HR] 4.62, 95% confidence interval [CI] 1.11-19.21), as was N1 disease (HR 4.50, CI 1.16-17.40).
A retrospective study of 50 patients by Uchida et al found that patients with preoperative jaundice had poorer survival than those without jaundice (5-year survival 57.2% vs. 100%, P < 0.01). Similarly, Carter et al reported that patients with pancreaticobiliary ampullary adenocarcinomas, whose survival was worse than that of patients whose tumors had intestinal histology, were more likely to present with jaundice.
In a series from Johns Hopkins, operative blood transfusions conferred a poorer 5-year survival rate on univariate analysis but not on multivariate analysis.
Akwari et al noted that papillary histologic features portended a more favorable prognosis, with a reported 40% survival rate at 5 years, versus only 16% in those with invasive lesions. The Cleveland Clinic experience also confirmed the favorable nature of papillary histology. Table 3 summarizes the outcomes for patients with involved lymph nodes.
Table 3. Summary of 5-Year Survival After Resection for Lymph Node Negative and Positive Carcinoma of the Ampulla of Vater
Patterns of failure
Unfortunately, most patients with carcinoma of the ampulla of Vater die of recurrent disease. Treatment fails in nearly 70% of patients with poor prognostic features, and these patients ultimately die of their disease.
Kopelson and associates described regional nodal recurrences in 3 of 12 patients with ampullary cancers following potentially curative resection. From pooled data on 80 patients with ampullary cancer, they found that 54% developed locoregional recurrence.
Because local and systemic failures remain problematic, physicians continue to be interested in offering adjuvant therapy. The relative rarity of this disease limits research in this area.[30, 31]
Willett and colleagues summarized their experience with adjuvant radiotherapy for high-risk tumors of the ampulla of Vater (risk factors included invasion into the pancreas, poorly differentiated histology, involved lymph nodes, or positive resection margins). Twelve patients received adjuvant radiotherapy (40-50.4 Gy) to the tumor bed and some received concurrent 5-fluorouracil (5-FU) as a radiosensitizer. Comparison of these patients with 17 patients who underwent surgical resection alone showed a trend toward better locoregional control with adjuvant radiotherapy, but there was no advantage in survival. Distant metastasis to the liver, peritoneum, and pleura was the dominant failure pattern in this group of patients.
Barton and Copeland reported on the M.D. Anderson Cancer Center experience of using postoperative chemotherapy for carcinoma of the ampulla of Vater. Seventeen patients received a variety of chemotherapeutic regimens (5-FU was used in combination with doxorubicin, carmustine, vincristine, methyl-lomustine, or mitomycin-C). Although no analysis was presented, the authors concluded that "no combination of drugs appeared to prolong life."
Sikora and colleagues presented their experience from a hospital in India in a retrospective review. Patients who underwent a pancreaticoduodenectomy with adjuvant chemotherapy and radiation did not do any better than the group treated with surgery alone.
Zhou et al reviewed the records of 111 patients at Johns Hopkins who underwent curative surgery for ampullary adenocarcinoma, 45% of whom also received adjuvant chemotherapy and radiation. In these patients, the improvement in survival with adjuvant treatment was not statistically significant (median overall survival: 21.6 vs. 13.0 months, P=0.092).
In a retrospective review, Chan and colleagues reported that 13 patients who received adjuvant chemotherapy (predominantly involving 5-FU, mitomycin-C, and doxorubicin) had a significantly better survival than 16 patients who underwent resection only.
Yeung and colleagues used neoadjuvant chemoradiotherapy for 20 patients with presumed carcinoma of the head of the pancreas, including 4 patients with duodenal/ampullary carcinomas. Interestingly, no residual tumor was found in pancreaticoduodenectomy specimens of the 4 patients thought to have had ampullary/duodenal carcinomas.
At Stanford University, all cases of periampullary carcinoma are discussed and reviewed in detail by a multidisciplinary team that includes surgical oncologists, medical oncologists, radiation oncologists, a pathologist, a gastroenterologist, and a radiologist. All resected tumors are reviewed. Patients with tumors with poor prognostic features (eg, involved surgical margins, lymph nodes, invasion of the pancreas, perineural invasion, or poor histologic grade) are enrolled in a single-arm investigational protocol to receive adjuvant radiotherapy (45 Gy) and concurrent protracted venous infusion of 5-FU (225 mg/m2/d) during the entire treatment course.
Patients with carcinoma of the ampulla of Vater may benefit from recent advances in the treatment planning and delivery of adjuvant and definitive radiotherapy for patients with pancreatic cancer, which have produced modest gains in survival.
Staging of ampullary cancer is critical to treatment. While ampullary polypectomy and ampullectomy have been performed successfully on some patients with ampullary cancer, this treatment is best reserved for patients whose overall performance status makes the risks associated with a formal pancreaticoduodenectomy excessive.
Carcinoma in situ has been diagnosed with increasing frequency. It has been associated with polypoid growth and is treated with endoscopic polypectomy. In these circumstances, remove the entire polyp and carefully study the base of the polyp to ensure that no cancer is at the margin. In the case of an incomplete excision, a prompt pancreaticoduodenectomy is essential. Patients who undergo polypectomy only should be monitored endoscopically at yearly intervals to guard against recurrence.
Pancreaticoduodenectomy is the procedure of choice for patients with resectable disease, but local recurrence plagues all surgical series, particularly when the pancreas has been invaded or lymph node metastases are discovered. In fact, whether major resection impacts survival in the setting of disease spread to the lymph nodes remains unclear. Postoperative irradiation of at least 45 Gy with 5-FU as a radiosensitizer is a reasonable treatment and reduces local recurrence in pancreatic cancer.
For patients with unresectable disease, endoscopic stenting to achieve biliary decompression is an appropriate palliative procedure. No established answer exists to the question of further therapy. Very little has been published on adjuvant treatment for locally advanced and advanced ampullary carcinoma. Confining one's approach to relief of symptoms is reasonable.
Given the paucity of effective standard treatment options, encourage patients to enroll in clinical trials. Radiotherapy, chemotherapy, and chemoradiotherapy have been tried, but response rates probably are low, and an effect on survival is questionable.